Endovascular Treatment of Intracranial Vein and Venous Sinus Thrombosis—A Systematic Review

Background: Cerebral venous sinus or vein thromboses (SVT) are treated with heparin followed by oral anticoagulation. Even after receiving the best medical treatment, numerous patients experience neurological deterioration, intracerebral hemorrhage or brain edema. Debate regarding whether endovascular treatment (EVT) is beneficial in such severe cases remains ongoing. This systematic review summarizes the current evidence supporting the use of EVT for SVT on the basis of case presentations, with a focus on patient selection, treatment strategies and the effects of the COVID-19 pandemic. Methods: This systemic literature review included randomized controlled trials (RCTs) and retrospective observational data analyzing five or more patients. Follow-up information (modified Rankin scale (mRS)) was required to be provided (individual patient data). Results: 21 records (n = 405 patients; 1 RCT, 20 observational studies) were identified. EVT was found to be feasible and safe in a highly selected patient cohort but was not associated with an increase in good functional outcomes (mRS 0–2) in RCT data. In observational data, good functional outcomes were frequently observed despite an anticipated poor prognosis. Conclusion: The current evidence does not support the routine incorporation of EVT in SVT treatment. However, in a patient cohort prone to poor prognosis, EVT might be a reasonable therapeutic option. Further studies determining the patients at risk, choice of methods and devices, and timing of treatment initiation are warranted.


Introduction
Cerebral venous sinus or venous thrombosis (SVT) is a rare but potentially severe cause of cerebral hemorrhage or cerebral venous infarction (incidence: 1.32 per 100,000 person-years (2.78 per 100,000 person-years in women 31-50 years of age)) accounting for approximately 0.5% of all stroke cases [1][2][3]. Various factors are associated with the development of SVT [1,4]. Recent publications have reported a considerably higher incidence of SVT in the COVID-19 pandemic because both COVID-19 (reported incidence: 8.8 per 10,000 infections over 3 months) and COVID-19 vaccination (leading to vaccine-induced immune thrombotic thrombocytopenia (VITT)) appear to increase the risk of SVT [5,6]. Figure 1 illustrates the anatomy of the cerebral dural sinus and the deep cerebral veins. Outcomes after SVT in general are favorable assuming early diagnosis and treatment initiation [8]. Treatment is challenging, and its success highly depends on rapid anticoagulation with unfractionated or low-molecular-weight heparin, even in cases of intracerebral hemorrhage [9,10]. However, probably because of a limited capacity to dissolve an extensive intravenous thrombus load, many patients show deterioration, and as many as 13% eventually die or remain severely disabled despite sufficient anticoagulation therapy [11][12][13]. Patients with coma or altered mental status, intracerebral hemorrhage (ICH), underlying malignancy or an infection of the central nervous system appear to be at risk [12]. Pregnant or postpartum women, chronic hypertension as well as superior sagittal sinus and cortical vein involvement seem to be associated with ICH complications in SVT [14].
The goal of this systematic review is to provide an overview on the current evidence supporting EVT strategies in patients with SVT. We aimed to identify potential selection criteria for patients who might benefit from an additional EVT. Furthermore, the roles of SARS-CoV-2 infections and VITT are discussed.

Materials and Methods
We performed a systematic literature search in the PubMed (20 May 2022) and Medline (20 May 2022) databases by using the following search terms: "sinus thrombosis AND endovascular," "sinus thrombosis AND thrombectomy," "[cerebral] venous thrombosis AND endovascular" and "[cerebral] venous thrombosis AND thrombectomy." For the sub-analysis of patients with SVT caused by SARS-CoV-2 infection or after COVID-19 vaccination, additional search phrases were identified: "COVID-19 AND endovascular (AND thrombosis)," "COVID-19 AND thrombectomy (AND thrombosis)," "vaccination AND endovascular" and "vaccination AND thrombectomy." All articles published online until 20 May 2022 were screened. Two independent raters performed the literature search (P.B. and H.H.). This review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) recommendations [60].
All identified publications were required to meet the following predefined inclusion criteria: (1) RCTs or retrospective studies, case series/case reports including more than five patients 18 years of age or older; (2) reported information on functional outcomes (modified Rankin scale (mRS) after discharge (not at the time of discharge)), death and complications (e.g., symptomatic intracranial hemorrhage or procedural complications); (3) inclusion of individual patient or study data only once (screening for repeated publications including identical cases); and (4) publication in English. In the analysis of EVT in patients with COVID-19 and VITT, only articles and manuscripts evaluating endovascular procedures (and the respective indications to treat patients) were eligible. We, therefore, did not consider registry data and meta-analyses reporting the frequency and the number of interventions without mentioning procedure-specific outcome parameters.

Results
A total of 456 records were identified and screened on the basis of the predefined search criteria ( Figure 2). Only 92 were eligible for full-text evaluation. Eventually, 21 records were eligible for inclusion (reasons for exclusion of records: n = 56-case reports or case series with fewer than five reported events; n = 14-no follow-up data or data on functional outcomes; n = 3-not written in English).
The goal of this systematic review is to provide an overview on the current evidence supporting EVT strategies in patients with SVT. We aimed to identify potential selection criteria for patients who might benefit from an additional EVT. Furthermore, the roles of SARS-CoV-2 infections and VITT are discussed.

Materials and Methods
We performed a systematic literature search in the PubMed (20 May 2022) and Medline (20 May 2022) databases by using the following search terms: "sinus thrombosis AND endovascular," "sinus thrombosis AND thrombectomy," "[cerebral] venous thrombosis AND endovascular" and "[cerebral] venous thrombosis AND thrombectomy." For the sub-analysis of patients with SVT caused by SARS-CoV-2 infection or after COVID-19 vaccination, additional search phrases were identified: "COVID-19 AND endovascular (AND thrombosis)," "COVID-19 AND thrombectomy (AND thrombosis)," "vaccination AND endovascular" and "vaccination AND thrombectomy." All articles published online until 20 May 2022 were screened. Two independent raters performed the literature search (P.B. and H.H.). This review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) recommendations [60].
All identified publications were required to meet the following predefined inclusion criteria: (1) RCTs or retrospective studies, case series/case reports including more than five patients 18 years of age or older; (2) reported information on functional outcomes (modified Rankin scale (mRS) after discharge (not at the time of discharge)), death and complications (e.g., symptomatic intracranial hemorrhage or procedural complications); (3) inclusion of individual patient or study data only once (screening for repeated publications including identical cases); and (4) publication in English. In the analysis of EVT in patients with COVID-19 and VITT, only articles and manuscripts evaluating endovascular procedures (and the respective indications to treat patients) were eligible. We, therefore, did not consider registry data and meta-analyses reporting the frequency and the number of interventions without mentioning procedure-specific outcome parameters.

Results
A total of 456 records were identified and screened on the basis of the predefined search criteria ( Figure 2). Only 92 were eligible for full-text evaluation. Eventually, 21 records were eligible for inclusion (reasons for exclusion of records: n = 56-case reports or case series with fewer than five reported events; n = 14-no follow-up data or data on functional outcomes; n = 3-not written in English).  One RCT (Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis; TO-ACT) compared EVT (n = 33) and standard care (i.e., anticoagulation; n = 34) in patients with anticipated poor outcomes (Table 1) [38], which were defined as at least one of the following risk factors: mental status disorder, coma state (Glasgow coma scale (GCS) < 9), ICH or thrombosis of the deep cerebral venous system. Patients with more than 10 days from diagnosis to potential randomization, pregnancy (women in the puerperium were eligible), thrombocytopenia (platelet count < 100 × 10 9 /L), as well as clinical or radiological signs of impending trans-tentorial herniation were excluded. EVT (mechanical thrombectomy with an AngioJet (Boston Scientific, Marlborough, MA, USA), stent retriever, aspiration techniques or microcatheter) in combination with local thrombolytic treatment (urokinase administered continuously for up to 72 h) did not differ from standard care in terms of functional outcomes (mRS, 0-1 at 12 months; 67% vs. 68%; risk ratio, 0.99 (95% CI, 0.71-1.18); Table 1 provides details and information on complications). Nyberg et al. (2017) have retrospectively analyzed their single-center cohort of patients with SVT and compared outcome data (mRS, 0-2 at 3 months) for patients treated with additional EVT (n = 29) to those receiving anticoagulation only (n = 37; 5-year time span (2011-2015)) [39]. The decision on whether to perform EVT was at the discretion of the treatment team and based on individual decision-making. The two treatment groups did not differ in outcome parameters (e.g., mRS, 0-2: 22% vs. 30%; mortality, n = 6 vs. n = 5; p = 1.0).
A total of 25 publications met the search criteria for COVID-19 and VITT-associated EVT in SVT. Of those, 14 records were excluded (because of lack of reported patient data, review articles and registry data without information on individual patients). Eleven records were eligible for analysis (Table 2) [61][62][63][64][65][66][67][68][69][70][71], comprising case reports and case series only. Of those, four case reports and case series presented data for four patients with COVID-19 and EVT [61][62][63][64]. The decision to perform EVT was made in cases with suspected poor prognosis, with criteria comparable to those described above. Aspiration in combination with local thrombolytic therapy was the preferred endovascular technique [61,62]. The overall outcome was poor [61][62][63].

Discussion
The overall outcome after SVT can be unfavorable in terms of functional independence and survival [8,11,72]. A total of 75-84% of patients eventually become functionally independent, with excellent functional recovery (mRS, 0-1) [8,11,72]. However, a considerable number of patients remain functionally dependent or disabled (22.2%) or die (up to 14.6%) [11,72]. To identify patients prone to poor prognosis, several risk factors have been identified (independent of treatment strategies): GCS < 9, presence of ICH, involvement of the deep cerebral venous system, mental status disorder (not specified; additional conditions such as underlying malignancy, cerebral or systemic infection, and requirement for hemicraniectomy also apply) [11,[72][73][74]. Neurological deterioration-as part of the natural course of the disease or due to factors such as heparin resistance-might necessitate an additional EVT approach to remove the thrombus load [75].
Retrospective and anecdotal data have demonstrated the safety and feasibility of EVT in selected patients, and have shown satisfying results [19,[39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]. Yet, because of their lack of a control group and their retrospective nature, those studies have been unable to demonstrate a treatment effect resulting in an outcome benefit. In addition, inconsistencies in the timing of the interventions, indications for surgical procedures such as decompressive hemicraniectomy, etiological considerations (e.g., malignancy or sepsis) and clinical complications interfering with outcomes (e.g., status epilepticus) make an interpretation difficult. To our knowledge, only one RCT (TO-ACT) has compared EVT to standard care in patients with SVT (again, with a suspected unfavorable prognosis, as described above). TO-ACT did not detect a modification of the treatment effect attributable to EVT (see Table 1 for inclusion criteria) [38]. The limitations of this trial include its small sample size (due to early termination recommended by the data and safety monitoring board because of futility), patient selection based on clinical presentations suspected to (and previously reported to) negatively influence outcomes and unrestricted use of available endovascular approaches and devices [38]. Therefore, non-significant but clinically relevant treatment effects as well as subgroups that might actually show considerable benefits remained undetected. In a meta-analysis using individual patient data (not including RCT data), EVT was associated with poor outcomes and mortality [76]. Because each treatment decision was made individually in each case (no clear indication; suspected poor prognosis), generalizability is limited. The baseline characteristics were poorer in EVT patients than in controls. Therefore, these retrospective results must be interpreted very cautiously. Important questions regarding patient selection (clinical versus imaging characteristics) and the timing of the intervention remain unanswered. Waiting until a patient is deteriorating might be too late.
Both COVID-19 and COVID-19 vaccination have been reported to be associated with an increase in SVT incidence [5,6]. Patients with COVID-associated SVT (4.2% of all COVIDassociated strokes) appear to be older, do not have specific risk factors and experience higher in-hospital mortality (up to 16.7%) [80,81]. In a New York cohort study, two of the 12 patients received endovascular local thrombolysis [5]. SVT associated with COVID-19 vaccination may be more severe and has higher reported mortality rates (39.2% as compared with approximately 2-5% in pre-pandemic SVT) [6]. The mechanism of pathogenesis (VITT; a prothrombotic state associated with an immunoglobin G reaction against PF4) predominantly occurs in adenovirus vector-type vaccinations (ChAdOx1 nCov-19 (AstraZeneca); recombinant adenovirus type 26 vector encoding S glycoprotein of SARS-CoV-2 (Johnson and Johnson/Janssen)) [6,82]. EVT might be reasonable in selected patients meeting the TO-ACT inclusion criteria (Table 1) [38,83]. Although observational data and case reports of EVT in those patients are scarce [65][66][67][68][69][70][71], these studies have indicated the feasibility and safety of EVT and have suggested that EVT can achieve good functional outcomes in a cohort with overall poor prognosis.
This systematic review is limited by the quality (and sample size) of the available data. The disadvantages of the TO-ACT trial have already been discussed. Because of the retrospective design of the remaining data, all the attributed limitations apply (e.g., selection bias or bias by indication) because the rationale for treatment allocation and the number of patients who were potentially eligible for treatment but were not considered are unknown. Therefore, the presented results and the conclusion require very cautious interpretation.
In conclusion, the available data do not support the routine use of EVT strategies in patients with SVT. In patients with a suspected poor outcome (meeting the TO-ACT inclusion criteria), EVT can be performed as part of individual healing attempts. EVT is feasible and safe and might possibly improve functional outcomes. No reasonable recommendation can be made regarding which endovascular technique to use (and in which cases). According to our own experience, patients with substantial thrombus material (without an early response to anticoagulation), those with ICH, those in need of intensive care, and those with VITT do benefit from EVT. Yet, whether patients with clinical and/or imaging risk factors might benefit from early treatment initiation (before deterioration occurs) remains unknown. Further RCTs are warranted to investigate treatment strategies, patient selection, and the timing of the intervention (using predefined therapeutic strategies and reproducible inclusion criteria).

Data Availability Statement:
There are no data beyond the analyzed publications, which became the basis for this systematic review.

Conflicts of Interest:
H.H. is coinventor of the Solitaire stent and the pRESET stent retriever and cofounder of phenox GmbH, femtos GmbH and CONTARA GmbH, which are medical device companies developing and/or selling products for the EVT of neurovascular disorders. All other authors declare no conflicts of interest in the context of this publication.